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Neuropsychiatric Aspects of HIV

Neuropsychiatric Aspects of HIV. University of Hawaii James Dilley, MD and Emily Leavitt, LCSW. Prevalence of MH Disorders among People with HIV/AIDS n = 1489. Vitiello et al. AJPsych 2003, 160:547-54 from “HIV Cost and Services Utilization Study—1996”. Depression in HIV.

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Neuropsychiatric Aspects of HIV

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  1. Neuropsychiatric Aspects of HIV University of Hawaii James Dilley, MD and Emily Leavitt, LCSW

  2. Prevalence of MH Disorders among People with HIV/AIDSn = 1489 Vitiello et al. AJPsych 2003, 160:547-54 from “HIV Cost and Services Utilization Study—1996”

  3. Depression in HIV • Most common dx in outpt settings • Concern re: diagnosis in medically ill • Emphasize cognitive/affective vs. neurovegatative signs/sxs • Assoc with CD4, soc support and  phys limitations and HIV sx • Excellent pharmacologic response • Give benefit of the doubt

  4. Pharmacotherapy of Depression in HIV

  5. Depression & Testosterone • 50% of men with Sx HIV/AIDS have deficiency and sx of hypogonadism: • Fatigue • Decreased libido • Decreased appetite • Decreased mood

  6. Screening Tests • Total Serum Testosterone: <300-400ng/dl • Serum Free testosterone: <5-7 pcg/ml • Tx: depot IM injections q ii wks (100-200mg IM; max 400 mg/wk) • Patch (5-10mg; 1-2 times daily) • Gel (25-100 mg to skin daily) • Can see mood improvement

  7. HIV produces at diff rates in CNS vs. plsma Diff phen/genotypes: esp later in disease All ARV’s not = in treating CNS cx May result in peripheral success (pVL) but central failure CNS: HIV’s Most Important Sanctuary Site

  8. HIV Neuropathogenesis Early and continuous seeding Importance of Blood Brain Barrier

  9. HAD: A Diagnosisof Exclusion • HIV antibody positive • No other treatable disorder known to be associated with mental status changes (e.g., no other CNS OI’s, trauma, metabolic disorders, etc.

  10. Diagnosis Requires (continued): • “Clinical findings of disabling cognitive and /or motor dysfunction interfering with occupation or activities of daily living” • Neuropsychological testing often needed, especially in early cases-- • (1 SD below age/education adjusted norms on 2/8 tests) AND • Either impairment in lower ext or fine motor skills or selfreported depression interfering with function

  11. Pseudo-Dementia • Depression in “dementia’s clothing” • Index of suspicion high if: • unremitting and detailed c/o memory pblms • “I don’t know” responses to cog questions: communicates distress/emphasizes disability • Behavior often incongruent w/level of complaint • In early stages of HIV disease • Frequently has past hx of psychiatric pblms

  12. Cognitive Functions A. Memory Short-term vs. delayed B. Concentration, Calculation and Constructional Ability C. Personality Change: alteration or accentuation of pre-morbid traits D. Language E. Judgement “Reasonable plans”

  13. Early Manifestations of HAD • Cognitive Memory Loss (names, historical details, etc.) Impaired Concentration (difficulty reading, loses track of conversation) Mental slowing (“not as quick,” less verbal) Confusion (time, especially)

  14. Early Manifestations of HAD (continued) • Behavioral Apathy, withdrawal, “depression” Agitation, hallucination • Motor Unsteady gait Bilateral leg weakness Tremor Loss of fine motor coordination

  15. Late Manifestations • Cognitive global dementia in all spheres confusion and distractability slow verbal responsiveness • Behavioral vacant stare disinhibition and restlessness organic psychosis

  16. Late Manifestations (cont.) • Motor general slowing truncal ataxia weakness: legs > arms pyramidal tract signs: spasticity, hyperreflexia

  17. Effect of HAART • Significant changes in the epidemiology of CNS disorders since HAART • In Sx illness • Studies are more consistent with subcortical dementia • In asx illness, NP findings are inconsistent • > Length of battery>NP deficits • Significance clinically is unclear

  18. Pathological Findings in CNS of AIDS Patients at Autopsy N = 1597 1984-1987 (No therapy) 1988-1994 (monotherapy) 1995-1996 (dual comb. therapy) 1997-2000 (triple comb. therapy) Vago L., et al. AIDS 2002, 16:1925-28

  19. Risk Factors for Cognitive Impairment in HIVCase Control: 90 HIV- ; 88 ASX; 94 SXCI = Scores of 2SD below the means of the control on 2 or more standard neuropsychological tests

  20. HAART N 69 CD 4 254 UVL 42% NPI 22% Non-HAART 61 342 20% p<0.01 54% p<0.0001 HAART Use & NP FunctionN = 130; Avg Age = 41; 42% NW; 82% AIDS Ferrando et al., AIDS, 1998, 12F 65-70 NOTE: IMP =  25D in the impaired direction of age-matched population-based norms HAART=  NRTI + Ritanavir, Indinavir or Nelfinavir

  21. Median HIV RNA levels for brain (for all available brain regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe McClernon D.R, et al. Neurology 2001, 57:1396-1401

  22. P  CSF < 200 >200 No No No Yes* No Yes No Yes* No No CSF  NP Status < 200 >200 Yes No Yes No Yes No Yes No Yes No Correlation of Plasma VL to CSF VL Brew (Aus) Ellis (US) MacArthur (US) Dore (US) DiStephano (Italy) ___________________________ * Correlation exists in ASX state

  23. Favorable CNS Characteristics of ARVs • % protein binding ( = better) • lipid solubility ( = better) • molecular weight ( = better) • inhibitory concentration ( = better)

  24. Medical Rx of HAD 1. Aggressive ARV: neuroprotective 2. Use combinations of 3, 4 or more Should include: • AZT, D4T, 3TC, Abac-NRTI • Nevirapine, Efavirenz-NNRTI • Indinavir - PI (best BBB penetrance)

  25. Factors Influencing Efficacy of ARV Rx: • Stage of HIV disease • Degree of CNS replication/resistance • Integrity of BBB • Specific treatment strategy/ARV choice

  26. Some NeuroprotectiveDisappointments Nimodipene  interaction with CAH Peptide T block gp-120 *Memantine NMDA antagonist/showing efficacy for ADV *Deprenyl Anti-oxidant/anti-poptotic Lexipafant PAF antagonist *some benefits

  27. Case History - “JC” ID: 42 y/o GWM architect admitted for agitation, irritability, decreased sleep, and grandiose delusions. Brought in by lover of 7 yrs. HPI Two mos intermittent confusion/ hypomania (rapid speech, disorganized thinking over last 3 days; focus on spiritual issues. Felt friends were trying to harm him, stated he had been cured of AIDS; claimed he was a millionaire. PMH HIV infected x 10 years; current CD4 count = 70. No OI’s. No previous psych hx.

  28. Case History - “JC” (cont.) MS: Alert, mildly agitated, unable to sit still. Speech: mildly pressured, loud, but interruptable. Thought process: overly inclusive, loose assns. Content: grandiose, “richest family in California,” had “cured himself of AIDS.” Some paranoia. Cognitive: 0 x 2. Memory: Imm = 4/4; 2/4 @ 5 mins. 3/4 with prompts. Attention: Serial 7’s = mult. Errors; WORLD backwards, “d-l-o-w.” Abstraction: Some concreteness. Construction: OK Insight: none Judgement: impaired

  29. Case History - “JC” (cont.) Diff Dx: Axis 1: Delirium due to HIV disease (293.0). Dementia due to HIV disease (294.1) R/O BAD R/O Toxic Psychosis Axis II: Deferred Axis III: AIDS

  30. Hospital Course LAB: MRI: Extensive cortical atrophy. LP: unremarkable Rx: Trilafon 2mg p.o. BID and 4 mg @ HS Valproic acid 250mg p.o. BID and 500 mg @ HS Ativan 0.5 mg p.o. BID and prn agitation

  31. Psychotropic Medication Use NOTE: Use among Af-Am was significantly lower than White or Hispanic. Vitiello et al. AJPsych 2003, 160:547-54 from “HIV Cost and Services Utilization Study—1996”

  32. Psychopharmacology in HIV Disease Consider geriatric dosing - “start low and go slow” Look for low-anticholinergic meds ConsiderPay special attention to Ritonavir (NORVIR - strong CYP3A4 inhibitor) Overall, anti-HIV meds are not problematic

  33. Pharmacotherapy of Anxiety Disorders 1. “Reactive” Anxiety -Lorazepam 0.5 mg B/TID Max: 4 mg q 4 hrs 2. Panic Disorders with or without Agoraphobia Paroxetine (Paxil) 10-40 mg/D Lorazepam for breakthrough 3. GAD - Paroxetine;Buspirone (Buspar) 5-10 mg BID - 20 mg TID Note: Buspirone is the “does not” drug: cause tolerance, physical dependence or a withdrawal syndrome, have abuse potential (hypnotic, muscle relaxant activity), work right away

  34. Ritonavir (Norvir)(Potent inhibitor of CP450, esp. 2D6 and 3A4) 1. AdjustAnti-depressants SSRI’s - initially  by 1/2 TCA’s - initially  by 1/2 to 1/3 Nefazodone and St. John’s Wort 2. Avoid Benzodiazepines Anti-psychotics Clonazepam (Klonopin) Clozapine Alprazolam (Xanax) Pimozide Diazepam (Valium) Flurazepam (Dalmane) Triazolam (Halcion) Zolpidem (Ambien) 2. Allow Temazepam (Restoril) Oxazepam (Serax) Lorazepam (Ativan) Bupropion (Wellbutrin)

  35. Methadone • Ritonavir and Nevirapine (and likely Efavirenz) has been shown to lead to significant withdrawal symptoms in stable methadone users • Should follow serum meth levels before & after initiation; may need to increase by 25-30%

  36. Other Pharm Issues • Sildenafil levels may be significantly raised by Ritonavir, Saquinavir and Indinavir--potentially serious CV effects (DNE 25mg) • Fatal case reports have been filed suggesting Ritonavir in combination with methamphetamine and Ecstasy (MDMA) was the cause of death • St. John’s Wort: may decrease PI’s

  37. ARV Classes

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